Author(s)

Manami Nishizawa, Kazuhisa Nishizawa

.
Department of Laboratory Medicine, Teikyo University School of Medical Technology, Tokyo, Japan.

Our recent coarse-grained (CG) molecular dynamics (MD) simulations of membranes with a hemifused-ribbon (λ-shaped) geometry showed curvature-driven demixing leading to enrich ment in dioleoyl-phosphatidylethanolamine (DOPE) in a negatively-curved region (at C = –0.8 nm^–1) of a DOPE/dipalmitoyl-phosphati-dylcholine (DPPC) membrane. Here we extend the analysis with respect to lipid composition and simulation time. Simulations of 12 – 20 μs effective time show that, compared with DOPE of the DOPE/DPPC system, a DPPC/dilinoleyl-PC [di(18:2)PC] membrane showed a similar degree of enrichment of di(18:2)PC in the curved region with C=–0.8 nm^–1. For the latter mixture, even weak negative curvatures (C=–0.5 – 0.6 nm^–1) caused significant degrees of di(18:2)PC enrichment. In agreement with recent studies of a planar bilayer, a ternary DPPC/ di(18:2)PC/cholesterol 0.42:0.28:0.3 mixture phase-separated into nanoscale raft-like liquid-ordered (L_o) and non-raft liquid-disordered (L_d) phases on a sub-microsecond time scale. The L_o domains were preferentially localized at planar portions, whereas the L_d domains were positioned mainly in curved regions of the membrane. Unlike binary dioleoylphosphatidylcho-line (DOPC)/cholesterol and DPPC/cholesterol mixtures, which showed only a slight enrich ment of cholesterol in the curved region, the ternary mixtures showed considerable migra tion of cholesterol and DPPC from the curved to the planar region. A pronounced degree of lipid segregation due to the preferential distribution of the L_d and L_o domains in the curved and planar regions, respectively, was observed even when the curvature of the fused monolayers (originally ‘cis’ leaflets) was weakened (C= –0.5 nm^-1). Overall, the results are consistent with theoretical predictions based on spontaneous curvature of the constituent lipids and the difference in rigidity between the L_d and L_o domains, whereas lipid-lipid interactions, such as PE-PE or DPPC-cholesterol, as well as propensity for interleaflet colocalization (registration) of the L_o and L_d domains appear to significantly amplify curvature-induced lipid demixing in the λ system. Intriguingly, for the DPPC/ di(18:2)PC/cholesterol ternary mixtures, a Lo/Ld domain boundary often moved to the branched point of the membrane, suggesting enhanced flexibility at the domain boundary. We hypothesize that curvature-driven lipid sorting and energetically favored localization of domain boundaries at sharp bends in the membranes may collaborate to assist intracellular lipid sorting.

Lipid Raft; Stalk Formation; Membrane Rigidity; Lipid Clustering; Lipid Sorting; Lipid Mixing; Hemifusion; Cholesterol-Rich Microdomain

Nishizawa, M. and Nishizawa, K. (2011) Coarse-grained simulations of branched bilayer membranes: effects of cholesterol-dependent phase separation on curvature-driven lipid sorting. Journal of Biophysical Chemistry, 2, 268-284. doi: 10.4236/jbpc.2011.23032.